Abnormal red blood cell (RBC) function, particularly decreased cell deformability, has been documented in sepsis, after trauma and during shock states. This decrease in RBC deformability is associated with, and has been shown to directly cause, impaired nutrient blood flow to various tissues, and thus might contribute to the development of the multiple organ dysfunction syndrome (MODS). However, the exact mechanisms and factors that lead to decreased RBC deformability remain to be determined. There are also studies that have documented more normal RBC deformability in women with cardiovascular disease than is seen in men with similar disease. We therefore wish to test the following two hypotheses: (1) that decreased RBC deformability after trauma-hemorrhage shock (T/HS) is secondary to gut injury and is mediated by factors carried in the intestinal lymph and;(2) that the changes in deformability following T/HS are less in females than in males. We will test the first hypothesis and investigate mechanisms by which toxic mesenteric lymph injures red cells. We propose to investigate the role of sex hormones as modulators of T/HS-induced RBC deformability in vivo. This is based on our pilot studies showing that female rats are more resistant to T/HS-induced changes in RBC deformability than male rats, as well as human studies indicating that RBC deformability is better preserved in pre-menopausal than post-menopausal women. Using in vitro studies, we propose to investigate the potential mechanisms responsible for the resistance of female rats to T/HS focusing on the role of sex hormones. Lastly, we propose to expand these animal studies to include male and female trauma patients. We believe these clinical studies will be important since they will allow us to compare the results observed in our T/HS model with those observed in trauma patients.